1-(Aminomethyl)cyclohexaneacetic acid, one of the 4-amino-3-substituted-butanoic acid derivatives, having the following structural formula is disclosed in U.S. Pat. Nos. 4,024,175 and 4,087,544 and has been called “gabapentin”, a generic name, due to its structural relation to γ-aminobutyric acid (GABA).
Gabapentin easily passes across the brain barrier. Owing to this, the compound is used as a medicine for the treatment of certain cerebral diseases such as certain forms of epilepsy, faint and hypokinesia as well as cranial traumas, and also for improving the cerebral functions in senile patients.
Moreover, U.S. Pat. No. 5,084,479 discloses that gabapentin is used for the treatment of neurodegenerative disorders such as Alzheimer's disease, Huntington's chorea or Parkinson's disease and amyotrophic lateral sclerosis. U.S. Pat. No. 5,025,035 discloses that gabapentin is used for the treatment of depression. U.S. Pat. No. 5,510,381 discloses that this compound is used for the treatment of mania and bipolar disorder. Furthermore, this compound, having an analgesic activity, is expected to be used as analgesics. Under these circumstances, there has been a greatly increased utility of gabapentin as the therapeutic agents for those diseases or disorders or conditions as recited above, in addition to cerebral diseases such as epilepsy and the like.
As stated above, gabapentin is a very effective drug for cerebral diseases such as epilepsy and the like, and it has an extremely low toxicity. However, in order to maintain the effect as expected, it has been administered to adults usually at a single daily dose of 900-1800 mg or in some cases a daily dose of up to 2400 mg in three divided doses. Thus, a single dose will be in the range of 300-600 mg or in some cases up to 800 mg.
Further, gabapentin has difficulties in that it is a drug having a strongly bitter taste and also a very poor fluidity and that an extremely high dosage should be required for administration in the dosage form of powders. Since gabapentin is very difficult to formulate because of its instability, gabapentin capsules now available in the oversea markets are those manufactured by a simple dry blending of gabapentin with necessary auxiliaries and subsequent encapsulating into hard capsules.
However, a single dose is as high as 300-600 mg or in some cases up to 800 mg as stated above, which necessitates large-sized capsules: for example, Capsule No. 0 should be applied to capsules having a content of 400 mg per capsule. Consequently, ingesting such capsules is difficult even for adults, much more for children. Although gabapentin capsules have already been marketed, it is still indispensable to attempt any improvement in compliance and easy administration of gabapentin, and a demand for a smaller-sized pharmaceutical preparation of gabapentin exists in the clinical field.
However, gabapentin in its aqueous solution shows a very poor stability so that autodegradation may be easily brought about. The mechanism of this autodegradation may be that the intramolecular condensation between the amino group and the carboxyl group within the gabapentin molecule is caused through a dehydration reaction to form 4-cyclohexylvinylpyrrolidone (the corresponding lactam form). In this regard, the autocondensation reaction rate may be variable depending upon storage temperature and can be far more accelerated as the temperature is elevated. Thus, this is the greatest reason why it has been difficult to manufacture a liquid pharmaceutical preparation of gabapentin.
On the other hand, another reason for difficulty in manufacturing a pharmaceutical preparation of gabapentin lies in that gabapentin itself is a powdery material having very poor compression-moldability and fluidity. Compression molding or granulation has been usually employed for small-sizing or fluidizing drugs which have such powder properties, and these molding properties should be improved with the aid of pharmaceutical auxiliaries. However, many of the auxiliaries to be applied for the purposes will accelerate the dehydration reaction between the amino group and the carboxyl group within the molecule of gabapentin to produce the corresponding lactam form, as the intramolecular condensation of gabapentin in its aqueous solution is accelerated. This dehydration reaction would be far more accelerated as the gabapentin powder is being more tightly compressed. Moreover, the reaction between gabapentin and such auxiliaries with lapse of time would be further accelerated by the use of water or an organic solvent in manufacturing a pharmaceutical preparation.
In short, it has been elucidated that the degradation of gabapentin with lapse of time due to the formation of the lactam is the phenomenon which shall be ascribed to the chemical structure of gabapentin itself and developed by the influence of water, irrespective of whether or not gabapentin is in the state of a solution or a solid.
It has been standardized in commercially available gabapentin capsules that an allowable content of the lactam up to the beyond-use date may be no more than 1.0% in view of safety. Accordingly, it is necessary in manufacturing a pharmaceutical preparation of gabapentin to prevent the formation of the lactam by retarding the dehydration reaction between the amino group and the carboxyl group within the molecule of gabapentin. On the other hand, it is a great problem to develop an adequate dosage form for easier ingesting, as discussed above.
Thus, in order to prepare a liquid pharmaceutical preparation of gabapentin, there have been made studies on, for example, controlling of pH, controlling of activity of water. Also, there have been attempted various methods, in order to form a smaller-sized solid pharmaceutical preparation of gabapentin. However, all of these prior art methods to manufacture solid or liquid preparations of gabapentin have not yet succeeded due to the presence of the lactam form found as the results of stability tests. Because of this, a pharmaceutical preparation of gabapentin now commercially available is limited to large-sized hard capsules only, although there has been a continuous need from the clinical field.
Such instability as encountered in manufacturing a gabapentin preparation has been also observed in other 4-amino-3-substituted-butanoic acid derivatives which are structurally analogous to gabapentin and have a structurally bulky substituent at the 3-position thereof similarly to gabapentin.
For example, 4-amino-3-p-chlorophenyl)butanoic acid, which is represented by the following structural formula and called “baclofen” in a generic name.
and 5-methyl-3-aminomethyl-hexanoic acid, which is represented by the following structural formula and called “pregabalin” in a generic name,
are also a drug which has very poor compression-moldability and fluidity like gabapentin. Compression molding or granulation used for small-sizing or fluidizing the drug should be improved with the aid of pharmaceutical auxiliaries. However, many of the auxiliaries to be applied to compression molding tend to react with gabapentin with lapse of time to form 4-cyclohexylpyrrolidone (the corresponding lactam form) by accelerating the dehydration reaction between the amino group and the carboxyl group within the molecule of the compound. This dehydration reaction would be far more accelerated as the compound is being more tightly compressed and would be further accelerated by the use of water or an organic solvent in manufacturing a pharmaceutical preparation, as is the case of gabapentin. It may be said that the mechanism of degradation by the autocondensation is peculiar to the 4-amino-3-substituted-butanoic acid derivatives having a structurally bulky substituent at the 3-position thereof.
To the contrary, in γ-aminobutyric acid derivatives having no or a less bulky substituent at the 3-position thereof, such as γ-aminobutyric acid or 4-amino-3-hydroxy-butanoic acid, the dehydration reaction is not brought about even when maintained in a dried state such as at a temperature of 105° C. over 2-3 hours, and the formation of 4-cyclohexylpyrrolidone (the corresponding lactam form) is not observed. In other words, in the 4-amino-3-substituted-butanoic acid derivative wherein the substituent at the 3-position thereof has a bulky structure, the dehydration reaction could easily be brought about between the amino group and the carboxyl group within the molecule.
In view of the aforesaid background, for drugs which are 4-amino-3-substituted-butanoic acid derivatives, including gabapentin, having a structurally bulky substituent at the 3-position thereof, there have been desired a new pharmaceutical preparation containing said drugs which has an excellent storage stability in the form of liquid preparations or in a small-sized or fluidized dosage form such as tablets or granules for easier ingestion and a process for manufacturing the same.